HectD1 Controls Hematopoietic Stem Cell Regeneration by Coordinating Ribosome Assembly and Protein Synthesis

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Mar 12

PMID 33711283

Citations 25

Authors

Kaosheng Lv

Chujie Gong

Charles Antony

Xu Han

Jian-Gang Ren

Ryan Donaghy

Ying Cheng

Simone Pellegrino

Alan J Warren

Vikram R Paralkar

Wei Tong

Affiliations

Soon will be listed here.

Abstract

Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains poorly understood, as are approaches to restore hematopoietic stem cell (HSC) function loss because of defective ribosome biogenesis. Here we reveal a role of the E3 ubiquitin ligase HectD1 in regulating HSC function via ribosome assembly and protein translation. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and ex vivo maintenance concomitant with reduced protein synthesis and growth rate under stress conditions. Mechanistically, HectD1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Hectd1 loss leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, resulting in 60S/40S joining defects. Importantly, Znf622 depletion in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. These findings highlight the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration.

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